4-165088507-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001100389.2(TMEM192):​c.535G>C​(p.Glu179Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

TMEM192
NM_001100389.2 missense

Scores

7
9
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95
Variant links:
Genes affected
TMEM192 (HGNC:26775): (transmembrane protein 192) Enables protein homodimerization activity. Located in several cellular components, including late endosome; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM192NM_001100389.2 linkc.535G>C p.Glu179Gln missense_variant Exon 4 of 6 ENST00000306480.11 NP_001093859.1 Q8IY95-1
TMEM192XM_011531718.4 linkc.440-2819G>C intron_variant Intron 3 of 4 XP_011530020.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM192ENST00000306480.11 linkc.535G>C p.Glu179Gln missense_variant Exon 4 of 6 1 NM_001100389.2 ENSP00000305069.4 Q8IY95-1
TMEM192ENST00000506087.5 linkc.523G>C p.Glu175Gln missense_variant Exon 5 of 7 2 ENSP00000425335.1 Q8IY95-2
TMEM192ENST00000505095.1 linkc.112G>C p.Glu38Gln missense_variant Exon 5 of 6 3 ENSP00000424590.1 D6RAZ6

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.535G>C (p.E179Q) alteration is located in exon 4 (coding exon 4) of the TMEM192 gene. This alteration results from a G to C substitution at nucleotide position 535, causing the glutamic acid (E) at amino acid position 179 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Uncertain
2.9
M;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.4
N;N;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.85
MutPred
0.65
Gain of catalytic residue at C182 (P = 0.1242);.;.;
MVP
0.20
MPC
0.15
ClinPred
0.96
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166009659; API